Abstract
Fluorouracil has been useful in the treatment of a wide variety of solid tumors, including cancers of the gastrointestinal tract and breast, for more than 40 years. Despite the introduction of newer agents such as irinotecan and oxaliplatin, fluorouracil continues to be an integral component of treatment regimens for colorectal cancer. Further, the ability to modulate its biochemical effects and activity through alterations in administration schedule or concomitant use of other agents has been demonstrated through numerous clinical and preclinical investigations. Most recently, these understandings have provided the basis for efforts to improve therapeutic selectivity and efficacy of the fluoropyrimidines by delivering fluorouracil as a prodrug and with inhibitors of dihydropyrimidine dehydrogenase (DPD).
Fluoropyrimidines in Cancer Therapy is 1 in a series of books on cancer drug discovery and development. This book covers a relatively broad range of topics related to the fluoropyrimidines, with an emphasis on the activation and inactivation pathways for fluorouracil and their relationship to its cytotoxic effects, mechanisms for modulating fluoropyrimidine disposition and activity, and clinical experiences with fluorouracil and its prodrugs in treatments for gastrointestinal malignancies. Although the pharmacology of fluorouracil is described in several chapters, some background knowledge is required, since the first chapter highlights some detailed aspects of modulation of the drug's anabolism and catabolism in an overview of these processes. This would be a difficult text for an individual who is unfamiliar with the fluoropyrimidines to use as an initial pharmacology resource.
The book is comprised of 24 chapters, which are split between summaries of preclinical and clinical data, with a slightly greater contribution of information toward clinical findings. Updates of clinical experiences, though, are generally limited to brief summaries of the nature and results of key clinical trials in operable and metastatic colorectal cancer. Early chapters address mechanisms of action, modulation strategies with leucovorin and DPD inhibition, and fluorouracil treatment schedules and combination therapies, whereas the later chapters summarize findings from clinical trials of fluorouracil and its prodrugs (e.g., uracil—ftorafor, eniluracil, capecitabine, S-1) in colorectal cancer. As thymidylate synthase is considered the major target of drug action, 2 chapters review mechanisms that regulate the expression of thymidylate synthase and thymidylate synthase gene expression. In addition, 1 chapter is devoted to more recent knowledge of the effects of fluorouracil on Fas-mediated apoptotic signaling and the role of p53 in tumor response to fluorouracil.
The scope of the content appropriately reflects the perspective of a book developed on a theme of drug discovery and development in that it explains the underlying mechanisms, rationale, and preclinical findings that have led to logically designed fluorouracil-based treatment regimens and improved clinical outcomes. The historical development of oral fluoropyrimidines and results of recent clinical trials are presented as well. Three of the chapters discuss capecitabine, specifically, with regard to its molecular pathways, preclinical pharmacology, and brief summaries of clinical trials. Therefore, this book would not be expected to and does not provide a comprehensive discussion of fluoropyrimidine pharmacokinetics or toxicities. These aspects are presented in part and variably throughout the book in the context of reviews of studies with oral fluoropyrimidines. A chapter on DPD emphasizing relationships between DPD activity and polymorphisms and fluorouracil pharmacokinetics and toxicity provides a concise overview of this information, but lacks the detail that a reader with a specific interest in pharmacogenetics and fluoropyrimidines might appreciate. Similarly, a chapter discussion of locoregional administration titled Hepatic Artery Infusion is somewhat limited to the clinical feasibility and results with this approach for colorectal liver metastases. On the other hand, the chapters on noninvasive studies of fluoropyrimidines and preclinical model systems for studying antitumor activities, as well as discussions of and references to research methodologies throughout the book, would be helpful to readers who are interested in pursuing these types of investigations.
Several internationally recognized, authoritative researchers contribute to the book in areas of their expertise, and the editor has an exceptional record of accomplishment and publication in the field of anticancer drug development and pharmacology. Overall, the book reads as a compilation of reviews and updates of preclinical and clinical fluoropyrimidine research. As such, there are frequent occasions of content overlap; however, the unique perspectives of the individual authors generally make this seem more interesting than redundant. One drawback of this approach is the relative lack of a true systematic presentation of the material. Multiple different figures of drug metabolism pathways that appear throughout the book illustrate this feature. Typographic errors, which stand out particularly in the early chapters, are somewhat distracting and also indicate that the review and coordination of material could be improved. Chapter reference citations are relevant and useful, but as in the case of most books, do not include work published during the past 2 years.
Fluoropyrimidines in Cancer Therapy would be a good reference for readers who are involved in clinical or preclinical research with fluoropyrimidines or clinicians who are interested in gaining a better understanding of the historical development of these agents, mechanisms of fluorouracil biochemical modulation, rational strategies to optimize drug combinations, or the current status of clinical trials of investigational oral fluoropyrimidines. At a price of $165, the value of this book is greatest with regard to the perspective that it provides information on historical and future development of these agents rather than as a source of recent clinical trial results. Since no comparable books are currently available, this would be a good reference to have at an institution where these investigations are performed.